There are over one million cases of cancer diagnosed each year in the United States and numerous approaches of therapy including systemic chemotherapy, radiation and surgical resection. Given that systemic chemotherapy and radiation interact with healthy tissue, complications and toxicity often result. Targeted drugs are now being used and produce a lower rate of complications. Ablative approaches, including microwave, radiofrequency and cryogenic therapies have been used; however, these methods are often not selective and tissues and organs surrounding or below the tumor can be affected.
According to the National Institute of Health, 30,640 people were diagnosed with primary liver cancer (hepatocellular carcinoma, HCC) and 142,820 people were diagnosed with colorectal cancer in the U.S. in 2013. Seventy-five percent of these will metastasize to the liver. Liver resection and transplant are the only curative means; however, only small numbers of patients are eligible. Systemic chemotherapy for primary and metastatic tumors in the liver is ineffective, having a response rate of about 20% and a survival benefit of 10.7 months vs. 7.9 months over symptomatic care.
Catheters are commonly used in medicine for delivery of fluids, therapeutics, and implants, and in sampling tissues and bodily fluids. Catheters can be constructed with balloons or other tools to dilate tissue, block fluid flow or isolate segments of the anatomy, such as in treatment of the cancers described above.
Trans-Arterial Embolization therapy is the transvascular injection of drug and/or embolic agents directly into the tumor vasculature using a microcatheter. Embolization therapy causes a shutdown of blood flow and, when drug or radioactivity is present, simultaneous release of high concentrations of drug or radioactivity. The technique is also noted for its very low level of toxicity.
In the early 1980's, transarterial chemoembolization (TACE) began to be used as a selective cancer therapy. In this method, chemotherapeutic and embolic agents are injected directly into the vasculature of the tumor, a technique that is most common for the treatment of hepatocellular carcinoma. More recently, transarterial radioembolization (TARE) has been used clinically. In this method, radioactive embolic particles, typically yttrium-90 (y90), are injected rather than chemotherapeutic agents. Although the liver is a common target for TACE and TARE, other organs, including, but not limited to, the pancreas, lung, kidney, prostate, stomach, colon and head and neck have been treated using these methods. Chemoembolization was established as a standard of care for intermediate stage hepatocellular carcinoma in 2006.
Numerous studies have demonstrated transarterial embolization to be effective on a number of primary cancers and to have better performance than chemotherapy for both HCC and metastatic colorectal cancers in the liver; however, studies show inconsistent outcomes with reported tumor responses from 15% to 85%. Although anatomical and individual differences are clearly of significance in between-patient variation, clinical studies, each of which include a range of patients, show very different outcomes, indicating that there currently is little procedural optimization or standardization.
The above procedures are accomplished by inserting a small catheter into the femoral artery at the groin and navigating it into the liver vasculature, typically the hepatic artery, then into the right or left lobe of the liver or more selectively into particular segments of the liver or super-selectively directly into or adjacent to the tumor. Super-selective transarterial delivery of antitumor agents into the tumor vasculature has become state-of-the-art and requires catheters that can reach into small vessels. Presently, standard microcatheters, typically at or about 3 Fr are used to inject antitumor agents into the target vasculature. These standard microcatheters rely on normal blood flow as the means by which the embolic agent moves into the tumor and systolic pressure as the packing force. However, the injection pressure is typically higher than the blood pressure and blood flow can be reversed. When this happens, the cancer agent flows in a retrograde direction with respect to normal blood flow and away from the tumor, with a concomitant risk of delivery of the anti-cancer therapy to organs that can be damaged by these toxic agents. This situation also results in loss of an unknown amount of drug.
The endpoint of the above procedures is determined by physicians' visual observation and can range between fully embolized to partially embolized with the amount of dose delivered being highly variable. Retrograde and anterograde reflux, distribution, packing, quantity of dose delivered and procedure endpoint are variables that can be highly dependent on the rate and pressure of injection, the selection of the type of endpoint, the patient's systolic pressure and the operator. As such, clinical trials using TACE to treat hepatocellular carcinoma have demonstrated wide variations in tumor response. The most significant problems that occur with the current means of delivery and methods of embolization therapy include inconsistent efficacy and non-target embolization.
Using standard straight-tip catheters, non-target embolization in the retrograde direction can be caused when the pressure of injection exceeds the systolic blood pressure and the embolic agents flow backwards over the catheter and into the general circulation. Anterograde reflux and non-target embolization occurs when the embolic agents flow into distal vasculature, through arteriovenus shunting and into the venous circulation. This can easily occur because venous blood pressure on average is about 10 to 15 mmHg as compared to arterial diastolic blood pressure of about 80 mmHg.
When therapeutic agents are delivered into the vasculature of a target structure using the normal anterograde blood flow to carry the therapy to the target, injection rate and pressure of the therapy must be carefully controlled in relation to the flow volume and pressure of blood to avoid retrograde reflux of drug backward over the catheter and into the general circulation. In particular, when injecting embolic agents into the vasculature of a tumor, pressure distal to the catheter tip continues to increase as embolization progresses, causing a resistance that prevents embolic agents from filling the target vasculature and the possibility of retrograde reflux and non-target embolization. It would be desirable to eliminate this retrograde reflux, non-target embolization, and the inconsistent dosages that are delivered to targets with current state of the art procedures. It would be further desirable to eliminate the low levels of particle distribution and density throughout the target vasculature. It would be still further desirable to replace current delivery devices that are not always capable of fully isolating the target vasculature and often do not allow the operator to control pressure, flow rate and other parameters associated with therapeutic delivery.
The present state-of-the-art embolization therapy for tumors in the liver relies on high volume forward flow from the hepatic artery to deliver embolization agents into the tumor. However; distal embolization of larger capillaries causes: (1) high intra-tumor vascular pressure, (2) high pressure in arteries feeding the tumor, (3) proximal reflux backwards over the delivery catheter, (4) increased anterograde bypass in distal hepatoenteric arteries and (5) poor filling and distribution of embolic agents in the tumor. This situation results in an uncontrollable number of particles entering the tumor and procedural high variability.
Problems with the current method of embolization therapy that cause inconsistent outcomes include: variable procedural endpoints, unknown quantity of dose delivered, reflux of embolization agents into the general circulation, anterograde bypass of embolization particles into the general circulation, non-target embolization, rising intra-tumor arterial pressures during the initial stages of embolization and catheter movement during injection. The current delivery catheters are unable to control many of the above mentioned variables, making any standardization of the current procedures difficult or impossible to achieve.
The following patents and published patent applications provide some examples of the current state of this art. U.S. Pat. No. 5,647,198 describes a catheter with a pair of spaced apart balloons that define an intra-balloon space. A lumen passes through the catheter and exits within the intra-balloon space allowing injection of drugs, emulsions, fluids and fluid/solid mixtures. A perfusion lumen or bypass extends from a location proximal to the proximal balloon and to the distal tip to allow shunting of blood past the inflated balloons. U.S. Pat. No. 5,674,198 describes a two balloon catheter that is designed for treating a solid tumor. The balloons are positioned to isolate the blood flow into the tumor and allow injection of a vaso-occlusive collagen material to block the tumor blood supply. Clifton et al. (1963) Cancer 16:444-452 describes a two balloon catheter for the treatment of lung carcinoma. The four lumen catheter includes a lumen for independent injection in the space between the balloons. Rousselot et al. (1965) JAMA 191:707-710 describes a balloon catheter device for delivering anticancer drugs into the Liver. See also U.S. Pat. Nos. 6,780,181; 6,835,189; 7,144,407; 7,412,285; 7,481,800; 7,645,259; 7,742,811; U.S. App. No. 2001/008451; U.S. App. No. 2001/0041862; U.S. App. No. 2003/008726; U.S. App. No. 2003/0114878; U.S. App. No. 2005/0267407; U.S. App. No. 2007/0137651;U.S. App. No. 2008/0208118; U.S. App. No. 2009/0182227; and U.S. App. No. 2010/0114021.
What is needed and is not provided by the prior art is a delivery system and method that enable optimization and standardization of treatment delivery, such as by delivering a known quantity of embolic agent to a prescribed target area, and elimination of non-target embolization.